Nigrostriatal {alpha}-synucleinopathy induced by viral vector-mediated overexpression of human {alpha}-synuclein: A new primate model of Parkinson's disease.

Research output: Contribution to journalArticle

Abstract

We used a high-titer recombinant adeno-associated virus (rAAV) vector to express WT or mutant human alpha -synuclein in the substantia nigra of adult marmosets. The alpha -synuclein protein was expressed in 90-95% of all nigral dopamine neurons and distributed by anterograde transport throughout their axonal and dendritic projections. The transduced neurons developed severe neuronal pathology, including alpha -synuclein-positive cytoplasmic inclusions and granular deposits; swollen, dystrophic, and fragmented neuritis; and shrunken and pyknotic, densely alpha -synuclein-positive perikarya. By 16 wk posttransduction, 30-60% of the tyrosine hydroxylase-positive neurons were lost, and the tyrosine hydroxylase-positive innervation of the caudate nucleus and putamen was reduced to a similar extent. The rAAV-alpha -synuclein-treated monkeys developed a type of motor impairment, i.e., head position bias, compatible with this magnitude of nigrostriatal damage. rAAV vector-mediated alpha -synuclein gene transfer provides a transgenic primate model of nigrostriatal alpha -synucleinopathy that is of particular interest because it develops slowly over time, like human Parkinson's disease (PD), and expresses neuropathological features (alpha -synuclein-positive inclusions and dystrophic neurites, in particular) that are similar to those seen in idiopathic PD. This model offers new opportunities for the study of pathogenetic mechanisms and exploration of new therapeutic targets of particular relevance to human PD.

Details

Authors
Organisations
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Neurosciences
Original languageEnglish
Pages (from-to)2884-2889
JournalProceedings of the National Academy of Sciences
Volume100
Issue number5
Publication statusPublished - 2003
Publication categoryResearch
Peer-reviewedYes